PROJECT SUMMARY Background: Fatigue is a common symptom in older adults, but accurate assessment and measurement of fatigue is confounded by perception and self-pacing of daily tasks. The concept of fatigability anchors perceived or performance-based fatigue to a specific activity, and thus may be a more reliable and discriminating indicator of health and risk of functional decline with aging. Reliable, valid measures of fatigability are needed to support new insights into mechanisms of aging and disease pathophysiology, and may serve as important outcome measures related to benefit or harm in future clinical trials. Accordingly, this proposal will define measures of perceived and performance fatigability using existing data collected longitudinally in the Baltimore Longitudinal Study of Aging (BLSA), combined with new measures to enhance validity and reliability testing. Given the breadth and depth of data already collected in the BLSA, these fatigability measures will be evaluated, independently and together, with a broad range of factors that will provide a greater understanding of the underlying mechanisms of fatigability by identifying a link with longitudinal changes in energy regulation and daily physical activity. Methods: To evaluate cross sectional and longitudinal characteristics of fatigability in older adults, we propose to assess reliability, construct, convergent/divergent, discriminant, and predictive validity and criteria for meaningful change in three candidate measures of fatigability in older adults participating in the BLSA: slowing during the 400m walk, perceived exertion during a standardized treadmill walk, and the Pittsburgh Fatigability Scale (PFS). We will also investigate potential whole-organism contributors to, and consequences of, fatigability including daily physical activity, aerobic capacity, walking efficiency, multimorbidity, and resting metabolic rate. We hypothesize that: (i) all three measures will have high test-retest reliability, and discriminate and predict longitudinal change in self-reported and performance physical function better than traditional measures of self-reported fatigue, and (ii) the magnitude of change in physical activity, multimorbidity, and energy regulation will be associated with corresponding changes in all three fatigability measures. Output: The information obtained from this research will provide critical evidence in the development of valid measures of fatigability using multiple candidate measures of fatigability, extensive indicators of potential population strata and cofactors, and novel measures of community based physical activity and metabolic efficiency. Validating measures of fatigability will improve use in the clinical setting and provide important outcome measures for future clinical trials. Understanding the physiological mechanisms of fatigability will shed light on the temporal associations among fatigability, physical activity, and functional decline in the pathway from robust health to functional limitations and define the critical threshold at which fatigability seriously limits the ability to maintain independence later in life.